Effect of low-dose naltrexone for long COVID: a systematic review and meta-analysis.

Abstract

Long covid is a debilitating chronic condition, and the effect of low-dose naltrexone (LDN) on its symptoms is unclear. We aimed to determine the effectiveness of LDN on symptoms of long covid. Systematic review and meta-analysis. PubMed, Embase and Cochrane Library for published studies; ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) for registered ongoing studies were searched through 5 May 2026. We included randomised controlled trials and pre-post studies of patients with long covid reporting on fatigue, quality of life, cognitive symptoms or function and other long covid symptoms. Two independent reviewers used standardised methods to search, screen and select included studies. Risk of bias was assessed using the Newcastle-Ottawa Scale. Meta-analysis was conducted using random effects models. Of 397 titles and abstracts screened, no randomised controlled trials were identified. Four observational pre-post studies from the USA and Ireland (n=155) met inclusion criteria. LDN doses varied from 1 mg/day to 6 mg/day. Pooled pre-post analyses showed moderate effects for reducing fatigue (Hedges' g=-0.74; 95% CI -1.11 to -0.37; p<0.001), brain fog (Hedges' g=-0.53; 95% CI -1.01 to -0.05; p=0.03) and improving sleep quality (Hedges' g=-0.60; 95% CI -0.91 to -0.30; p=0.0001), and large effects for pain (Hedges' g=-0.93; 95% CI -1.29 to -0.57; p<0.001) and daily functioning (Hedges' g=-0.93; 95% CI -1.29 to -0.57; p<0.0001) in favour of LDN. Heterogeneity ranged from 0% to 62%. No serious adverse events were reported in the two studies that assessed safety. Limited evidence from small pre-post studies suggests LDN may improve fatigue, cognition, sleep, pain and functioning in long covid. However, certainty of evidence is low. Well-powered trials are needed to confirm efficacy, determine dosing and duration and identify subgroups most likely to benefit. https://doi.org/10.17605/OSF.IO/C2VKX.